After receiving a Ph.D. from Johns Hopkins University in 1953, Greengard became director of the biochemistry department at Geigy Research Laboratories (1959–67) in Ardsley, New York, and held professorships at Albert Einstein College of Medicine (1961–70) and Yale University (1968–83). In 1983 he became professor and head of the Laboratory of Molecular and Cellular Neuroscience at Rockefeller University.

When Greengard began his prizewinning work in the late 1960s, scientists recognized dopamine, noradrenaline, and serotonin as key neurotransmitters in a signaling process called slow synaptic transmission. Greengard showed that slow synaptic transmission involves a chemical reaction called protein phosphorylation; in that reaction a phosphatemolecule is linked to protein, changing the protein’s function. Greengard worked out the signal-transduction pathway that begins with dopamine. When dopamine attaches to receptors in a neuron’s outer membrane, it causes a rise in a second messenger, cyclic AMP. This molecule, in turn, activates an enzyme that adds phosphate molecules to other proteins in the neuron. Protein phosphorylation can affect the neuron in different ways, including its sensitivity to being triggered to fire off nerve signals. Greengard’s work helped provide a better understanding of certain neurological and psychiatric disorders and aided in the development of new drugs for their treatment.